Skin appearance and elasticity has always been a cosmetic concern for almost everybody. Skin protection against actinic radiations has become a great health concern over the past ten to twenty years. UV exposure results in the formation of noxious reactive oxygen species (ROS). Skin damages cannot only be life threatening, but they contribute for premature skin ageing. The most popular way by which UV damages are prevented is to block their penetration through the skin using sunscreen formulations. The notion that antioxidants may also be used to improve the therapeutic or cosmetic performance of dermatological formulations is more recent. Antioxidants would in that case have a role in neutralizing ROS or preventing their formation into the skin. Antioxidants include compounds such as ascorbic acid and complexes, tocopherol, tocopheryl acetate, retinol, retinyl palmitate, hydroquinone, proanthocyaniadins, butylated hydroxytoluene, butylated hydroxyanisole, astaxanthin, alpha lipoic acid, tocotrienols, certain proteins and coenzyme Qio. Each antioxidant may be used alone or in combination with each another as active ingredients or as stabilizing and preservation agents to protect other active ingredients against oxidative damages. Antioxidants may also be used alone or in combination with reducing agents such as L-cysteine or glutathione.
Antioxidants need to remain in their unoxidized form in order to be efficacious against ROS. Maintenance of antioxidants stability in solutions has been a challenge over the past years.
Ascorbic acid, also known as vitamin C, is certainly one of the most popular antioxidants. This vitamin is known for its general essential role in maintaining health. In dermatology, vitamin C is known for its implication in collagen synthesis as well as for its antioxidant function, which ultimately helps reduce the expression of skin ageing, translated into the appearance of fine lines or wrinkles in the skin. Vitamin C also has an anti-tyrosinase effect on the skin for skin whitening effect.
Vitamin C is a moderately strong reducing agent, which makes it unstable in aqueous solutions, especially at high pHs. It is particularly subject to oxidative degradation.
Water is one of the best solvents to dissolve ascorbic acid. Its limit of solubility appears to be about 330 mg/ml in water. Ascorbic acid is therefore relatively soluble in water. It is much less soluble in glycols such as propylene glycol (50 mg/ml) and in alcohols such as ethanol (10 mg/ml in absolute ethanol).
Although water is the best solvent to provide an ascorbic acid solution, it is paradoxically one of the worst to protect ascorbic acid against oxidative damages. A proportion of water needs to be replaced with another solvent that provides more stability.
The problem to be solved with ascorbic acid formulations has always been to find a compromise between solubilization and stability.
U.S. Pat. No. 5,140,043 discloses an ascorbic acid formulation that has a pH below 3.5, preferably below 2.5. A low pH insures that a high proportion of ascorbic acid remains in the protonated, uncharged form. The protonated form is more stable and more easily permeant through skin and mucosae membranes than the non-protonated counterpart. Metals also negatively influence the preponderance of the protonated form of ascorbic acid in a solution. A chelator may therefore be added in ascorbic acid solutions to stabilize the vitamin. The carrier in which the ascorbic acid is dissolved comprises an alkylene glycol, namely propylene glycol. The carrier further comprises hydroxyalkylcellulose, the polyhydroxyl function of which apparently participates in the typical reactions of alcohols. The proportion of water remains very high (more than 50% by weight), which may lead to a relatively rapid degradation at room temperature.
U.S. Pat. No. 4,983,382 discloses the use of polyhydric liquids to solubilize and stabilize ascorbic acid. A mixture of ethanol 55-65% and propylene glycol 20-25% is especially preferred for its excellent cosmetic properties. Water may be present in concentrations up to 12% without adversely affecting the stability of ascorbic acid solubilized in a mixture of alcohol and propylene glycol. The organic solvents, all combined, represent up to 90% by weight of a composition. The low water contents recommended does not appear to permit solubilization of more than 10% of ascorbic acid.
U.S. Pat. No. 6,124,348 proposes to combine ascorbic acid, a volatile organic solvent such as isodecane and a gelling base. The solvent does not react with or solubilize the vitamin. Such a suspension is applied to the skin. The skin moisture penetrates the suspension and solubilizes the ascorbic acid which then can permeate the skin layer. The solubility of ascorbic acid in the formulation is not dealt with in this patent.
Another type of dispersion of ascorbic acid is disclosed in U.S. Pat. No. 6,103,267. Again, this patent does not describe a solution of ascorbic acid.
Another approach to stabilize ascorbic acid solution has been to decrease water activity in the same. U.S. Pat. No. 5,736,567 discloses compositions wherein water activity is decreased below 0.85. The lowest water activity achieved with the descriptive examples has been 0.63. At this value, the water content is 21%, the ascorbic acid concentration is 3%, the polypropylene glycol content is 39.4% and polyethylene glycol content is 13% (all percentages given by weight of formulation). The aqueous phase is combined with an oil phase to provide a composition that has a “structure”. This particular formulation has been tested for its stability. After two months at 20° C., 0.7% of ascorbic acid has degraded which is fairly good compared to the same solution prepared with 28% water (3.5% degradation) and a composition also comprising 28% water but without the glycols (6.2% degradation). The concentration of ascorbic acid that may be present in these formulations is not higher than 10%.
U.S. Pat. No. 6,087,393 discloses a composition comprising ascorbic acid in a mixed glycerol carrier. The glycerol carrier comprises propylene glycol and butylene glycol, as well as a stabilizer which may be diethylene glycol monoethylether. The preferred proportions of propylene glycol, butylene glycol and diethylene glycol monoethylether are 25-80%, 5-30% and 5-10%, respectively. Ascorbic acid may be present in concentrations comprised between 2% and 15%. In these solutions, the major glycol component is clearly propylene glycol while butylene glycol is added as a solubilizing aid and diethylene glycol monoethylether is added in minor proportion as a stabilizer. The stability of these solutions is not excellent because, at best, the samples admittedly start to develop a yellowish colour after one month at room temperature.
Another approach to formulate and use ascorbic acid in dermatology has been not to deal with its stability. U.S. Pat. No. 5,953,584 proposes to provide separate compartments that are extemporaneously mixed together prior to use. One compartment comprises vitamin C, the other one comprises an aqueous phase. Once reconstituted by admixing the contents of both compartments, ascorbic acid is provided in a solution that is more alkaline than usual solutions of ascorbic acid. The limit of solubility of the vitamin achieved with such a solution is close to 50%. Further, once reconstituted, the ascorbic acid formulation comprises about half-and-half polyethylene glycol and water.
In view of the foregoing, there is still a need to develop a solubilized ascorbic acid in suitable concentrations, and which remains stable for a practical shipping and storage amount of time, and which keeps a clear substantially non-coloured visual aspect for the same amount of time.